JP2018522862A - Process for the preparation of xanthine-based compounds - Google Patents
Process for the preparation of xanthine-based compounds Download PDFInfo
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- JP2018522862A JP2018522862A JP2017566781A JP2017566781A JP2018522862A JP 2018522862 A JP2018522862 A JP 2018522862A JP 2017566781 A JP2017566781 A JP 2017566781A JP 2017566781 A JP2017566781 A JP 2017566781A JP 2018522862 A JP2018522862 A JP 2018522862A
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- linagliptin
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- 238000000034 method Methods 0.000 title claims abstract description 50
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 18
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 title abstract description 6
- 229940075420 xanthine Drugs 0.000 title abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000000460 chlorine Chemical group 0.000 claims description 7
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 36
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 31
- 229960002397 linagliptin Drugs 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- GGPNYXIOFZLNKW-ZJIMSODOSA-N (3r)-piperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CCCNC1 GGPNYXIOFZLNKW-ZJIMSODOSA-N 0.000 description 8
- GMSNIKWWOQHZGF-UHFFFAOYSA-N 3-methyl-9H-xanthine Chemical compound O=C1NC(=O)N(C)C2=C1N=CN2 GMSNIKWWOQHZGF-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- UHCUBOJGMLASBY-UHFFFAOYSA-N 2-(chloromethyl)-4-methylquinazoline Chemical compound C1=CC=C2C(C)=NC(CCl)=NC2=C1 UHCUBOJGMLASBY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- SUXMJAFXGNHBGY-UHFFFAOYSA-N 7-but-2-ynyl-8-iodo-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione Chemical compound CC1=NC(=NC2=CC=CC=C12)CN1C(=O)N(C=2N=C(N(C=2C1=O)CC#CC)I)C SUXMJAFXGNHBGY-UHFFFAOYSA-N 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- NBCKTRBIJQGFFE-UHFFFAOYSA-N 7-but-2-ynyl-8-chloro-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione Chemical compound C(C#CC)N1C(=NC=2N(C(N(C(C1=2)=O)CC1=NC2=CC=CC=C2C(=N1)C)=O)C)Cl NBCKTRBIJQGFFE-UHFFFAOYSA-N 0.000 description 4
- SJEXZCRZWVWXPY-UHFFFAOYSA-N 7-but-2-ynyl-8-chloro-3-methylpurine-2,6-dione Chemical compound CN1C(=O)NC(=O)C2=C1N=C(Cl)N2CC#CC SJEXZCRZWVWXPY-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- PEUGKEHLRUVPAN-RXMQYKEDSA-N (3r)-piperidin-3-amine Chemical class N[C@@H]1CCCNC1 PEUGKEHLRUVPAN-RXMQYKEDSA-N 0.000 description 3
- CPLWLMDNRLTZHK-UHFFFAOYSA-N 7-but-2-ynyl-3-methylpurine-2,6-dione Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2CC#CC CPLWLMDNRLTZHK-UHFFFAOYSA-N 0.000 description 3
- NDCIHQJKZBTATM-UHFFFAOYSA-N 8-iodo-3-methyl-7H-purine-2,6-dione Chemical compound IC1=NC=2N(C(NC(C=2N1)=O)=O)C NDCIHQJKZBTATM-UHFFFAOYSA-N 0.000 description 3
- RUMFUJPGIUKFFU-UHFFFAOYSA-N C(C#CC)N1C(=NC=2N(C(NC(C1=2)=O)=O)C)I Chemical compound C(C#CC)N1C(=NC=2N(C(NC(C1=2)=O)=O)C)I RUMFUJPGIUKFFU-UHFFFAOYSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- LNNXOEHOXSYWLD-UHFFFAOYSA-N 1-bromobut-2-yne Chemical compound CC#CCBr LNNXOEHOXSYWLD-UHFFFAOYSA-N 0.000 description 2
- JWEOEZZCZCCPJL-UHFFFAOYSA-N 4-methylquinazoline Chemical compound C1=CC=C2C(C)=NC=NC2=C1 JWEOEZZCZCCPJL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- SZDVVNIQCKMJQU-UHFFFAOYSA-N 7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione Chemical compound CC#CCn1cnc2n(C)c(=O)n(Cc3nc(C)c4ccccc4n3)c(=O)c12 SZDVVNIQCKMJQU-UHFFFAOYSA-N 0.000 description 1
- RCZJXCXNYGHNSR-UHFFFAOYSA-N 8-bromo-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione Chemical compound C1=CC=CC2=NC(CN3C(=O)N(C)C=4N=C(Br)N(C=4C3=O)CC#CC)=NC(C)=C21 RCZJXCXNYGHNSR-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- VHJYVXVTWWISQL-UHFFFAOYSA-N but-2-ynyl methanesulfonate Chemical compound CC#CCOS(C)(=O)=O VHJYVXVTWWISQL-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- -1 tert-butyloxycarbonyl (Boc) Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本発明はキサンチンをベースとする化合物の調製方法だけでなく、このような方法に有益な中間体に関する。【選択図】なしThe present invention relates not only to the preparation of xanthine-based compounds, but also to intermediates useful for such methods. [Selection figure] None
Description
本発明はキサンチンをベースとする医薬活性成分、即ち、リナグリプチンの調製方法だけでなく、このような調製に有益な中間体に関する。 The present invention relates not only to a process for the preparation of pharmaceutically active ingredients based on xanthine, ie linagliptin, but also to intermediates useful for such preparation.
1-[(4-メチル-キナゾリン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-(3-(R)-アミノ-ピペリジン-1-イル)- キサンチン（その国際的な非所有権の名称はリナグリプチンである）は、以下に示される下記の構造を有する。
今まで、その分子を合成するための幾つかの合成経路が幾つかの文献により記載されていた。
例えば、リナグリプチンの調製方法が文献WO 2004/018468及びWO 2006/048427に開示されている。
文献WO 2014/059938は相間移動触媒を伴ない、保護された(R)-ピペリジン-3-アミン誘導体を使用するリナグリプチンの更なる調製方法を記載している。WO 2014/059938 の方法はアミン保護基、例えば、tert-ブチルオキシカルボニル (Boc)保護及びその合成方法の後の段階で使用される中間体の脱離基保護を必要とする。
文献WO 2013/098775はリナグリプチンの更なる調製方法を記載している。(R)-ピペリジン-3-アミン (又はその塩酸塩) が好適な塩基（特にK2CO3 ）の存在下で不活性溶媒（特にDMF 又はMIBK）中で1-[(4-メチル-キナゾリン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-ブロモ-キサンチンと反応させるのに直接使用されてリナグリプチンを得ると言われている。しかしながら、文献WO 2013/098775 は1-[(4-メチル-キナゾリン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-ブロモ-キサンチンを中間体として使用することを開示しているにすぎない。
Until now, several synthetic routes to synthesize the molecule have been described by several documents.
For example, methods for preparing linagliptin are disclosed in documents WO 2004/018468 and WO 2006/048427.
The document WO 2014/059938 describes a further method for the preparation of linagliptin using a protected (R) -piperidin-3-amine derivative with a phase transfer catalyst. The method of WO 2014/059938 requires amine protecting groups, such as tert-butyloxycarbonyl (Boc) protection and intermediate leaving group protection used in later steps of the synthesis process.
The document WO 2013/098775 describes a further preparation method for linagliptin. (R) -piperidin-3-amine (or its hydrochloride) is 1-[(4-methyl-quinazoline) in an inert solvent (especially DMF or MIBK) in the presence of a suitable base (especially K 2 CO 3 ). -2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-bromo-xanthine is said to be used directly to give linagliptin. However, the document WO 2013/098775 uses 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-bromo-xanthine as an intermediate. It only discloses the use.
特に医薬目的のための、大規模な製造に適しているリナグリプチンの更なる調製方法を見い出すことが所望されている。 It is desirable to find a further preparation method of linagliptin that is suitable for large-scale production, especially for pharmaceutical purposes.
本明細書に大いに詳しく記載されている、方法は、如何なるアミン保護基を必要とせず、しかもリナグリプチンの調製のための有効な、短い、丈夫かつスケールアップできる方法を提供し、医薬目的及び医療目的の如き純粋なリナグリプチンの調製に特に適していることが今わかった。
従って、本発明はリナグリプチンの調製方法、このような方法に有益な中間体、並びに薬物としての使用のためのリナグリプチンの調製のためのその方法及び中間体の使用に関する。
更に、本発明はリナグリプチンの医薬組成物の調製方法に関するものであり、前記方法はi)本明細書に記載された方法に従ってリナグリプチンを調製し、そしてii) 医薬組成物を生成するためにリナグリプチンを一種以上の医薬上許される賦形剤と合わせることを含む。
The method, described in great detail herein, does not require any amine protecting group and provides an effective, short, robust and scaleable method for the preparation of linagliptin, for pharmaceutical and medical purposes. It has now been found to be particularly suitable for the preparation of such pure linagliptin.
Accordingly, the present invention relates to a method for preparing linagliptin, an intermediate useful for such a method, and the use of the method and intermediate for the preparation of linagliptin for use as a drug.
Furthermore, the present invention relates to a method for preparing a pharmaceutical composition of linagliptin, said method comprising i) preparing linagliptin according to the methods described herein, and ii) using linagliptin to produce a pharmaceutical composition. Combining with one or more pharmaceutically acceptable excipients.
本発明者らの研究に基づいて、脱離基としてのBrの他に、Cl又はＩが1-[(4-メチル-キナゾリン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-キサンチンの8位の脱離基として利用することができ、それらの相当する基質、即ち、1-[(4-メチル-キナゾリン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-クロロ-キサンチン及び1-[(4-メチル-キナゾリン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-ヨード-キサンチンが、好適な塩基（例えば、無機又は有機の塩基、例えば、Na2CO3 (炭酸ナトリウム) 、K2CO3 (炭酸カリウム) 、NaHCO3 (重炭酸ナトリウム) 又はKHCO3 (重炭酸カリウム)）の存在下で好適な溶媒（例えば、有機溶媒もしくは水性溶媒、又は溶媒の混合物、特に非プロトン性極性溶媒、例えば、NMP (N-メチル-2-ピロリドン) 、DMSO (ジメチルスルホキシド) 、DMAc (N,N-ジメチルアセトアミド) 又はDMF (N,N-ジメチルホルムアミド)）中でピペリジン-3-アミン [特に(R)-ピペリジン-3-アミン] 又はその塩 (例えば、二塩酸) 、好ましくは(R)-ピペリジン-3-アミン二塩酸塩と直接反応させられてリナグリプチンを良好な収率及び純度で得ることができる。
リナグリプチンの調製方法が本発明のカップリング反応を伴なう下記のスキーム１に概説される。
スキーム 1
Based on our study, in addition to Br as the leaving group, Cl or I is 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2- Butyn-1-yl) -xanthine can be utilized as a leaving group at the 8-position, and its corresponding substrate, namely 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl -7- (2-butyn-1-yl) -8-chloro-xanthine and 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl ) -8-iodo-xanthine is a suitable base (eg, an inorganic or organic base such as Na 2 CO 3 (sodium carbonate), K 2 CO 3 (potassium carbonate), NaHCO 3 (sodium bicarbonate) or KHCO 3 (potassium bicarbonate)) in the presence of a suitable solvent (eg an organic or aqueous solvent, or a mixture of solvents, in particular an aprotic polar solvent such as NMP (N-methyl-2-pyrrolidone), DMSO ( Dimethyl sulfoxide), DMA c (N, N-dimethylacetamide) or DMF (N, N-dimethylformamide)) piperidin-3-amine [especially (R) -piperidin-3-amine] or a salt thereof (eg dihydrochloric acid), preferably Can be reacted directly with (R) -piperidin-3-amine dihydrochloride to obtain linagliptin in good yield and purity.
A method for preparing linagliptin is outlined in Scheme 1 below with the coupling reaction of the present invention.
Scheme 1
本発明の或る更に詳しい実施態様において、本発明は以下の例示の例により実質的に記載されたプロセス、方法及び／又は個々のプロセス工程及び／又は個々の反応条件に関する。
リナグリプチンの調製方法が下記のスキーム２に概説される。一実施態様において、本発明は下記のスキーム２に実質的に示されるリナグリプチンを調製するための多工程合成方法に関する。その他の実施態様において、本発明はスキーム２の個々の工程のそれぞれ及びスキーム２の二つ以上の連続工程のあらゆる組み合わせに関する。また、本発明は、例えば、スキーム２に示される、中間体化合物に関する。
更に詳しい例において、合成（スキーム２）が好適な塩基及び好適な溶媒の存在下で、例えば、NMP 中のKHCO3 の存在下で、例えば、メタンスルホン酸ブト(but)-2-インイル(ynyl)エステル (8)による3-メチル-3,7-ジヒドロ -プリン-2,6-ジオン (7)のアルキル化で開始して化合物９を約94％の収率で得てもよい。次いで化合物９が例えば、DMF 中でNCS により塩素化されて化合物10を約83％の収率で得てもよい。また、塩素化がまたNMP 中で行なわれてもよく、これが化合物７から化合物10へのワンポット反応を可能にする。次いで、化合物10が好適な塩基及び好適な溶媒の存在下で、例えば、NMP 中のNa2CO3の存在下で2-クロロメチル-4-メチル-キナゾリン (11) と反応させられて7-ブト -2-インイル -8-クロロ-3-メチル-1-(4-メチル-キナゾリン-2-イルメチル)-3,7-ジヒドロ -プリン-2,6-ジオン (12) を78％の収率で得てもよい。
リナグリプチンを生成するための化合物12と(R)-3-アミノピペリジン二塩酸塩(13)のカップリング反応はNa2CO3、NaHCO3、又はKHCO3 のような異なる塩基を用いて作業し得る。このカップリング反応のために、異なる種類の非プロトン性極性溶媒が使用でき、NMP 、DMSO、又はDMF が挙げられるが、これらに限定されない。研究は塩基としてのNaHCO3 及び溶媒としてのNMP を使用することの組み合わせが転化率及び反応プロフィールのきれいさに関して最良の結果を与えることを示す。最後に、例えば、トルエン中のような再結晶による精製後に、リナグリプチンが77％の収率で99.2％の純度で得られる。
In certain further embodiments of the invention, the invention relates to processes, methods and / or individual process steps and / or individual reaction conditions substantially as described by the following illustrative examples.
The method for preparing linagliptin is outlined in Scheme 2 below. In one embodiment, the present invention relates to a multi-step synthetic method for preparing linagliptin substantially as shown in Scheme 2 below. In other embodiments, the invention relates to each of the individual steps of Scheme 2 and any combination of two or more sequential steps of Scheme 2. The present invention also relates to an intermediate compound shown in, for example, Scheme 2.
In a more detailed example, the synthesis (Scheme 2) is carried out in the presence of a suitable base and a suitable solvent, for example, in the presence of KHCO 3 in NMP, eg, but-2-ynyl methanesulfonate. Starting with alkylation of 3-methyl-3,7-dihydro-purine-2,6-dione (7) with ester (8), compound 9 may be obtained in about 94% yield. Compound 9 may then be chlorinated, for example, with NCS in DMF to give compound 10 in about 83% yield. Chlorination may also be carried out in NMP, which allows a one-pot reaction from compound 7 to compound 10. Compound 10 is then reacted with 2-chloromethyl-4-methyl-quinazoline (11) in the presence of a suitable base and a suitable solvent, for example, in the presence of Na 2 CO 3 in NMP to give 7- 78% yield of but-2-ynyl-8-chloro-3-methyl-1- (4-methyl-quinazolin-2-ylmethyl) -3,7-dihydro-purine-2,6-dione (12) It may be obtained at.
The coupling reaction of compound 12 and (R) -3-aminopiperidine dihydrochloride (13) to produce linagliptin can work with different bases such as Na 2 CO 3 , NaHCO 3 , or KHCO 3 . Different types of aprotic polar solvents can be used for this coupling reaction, including but not limited to NMP, DMSO, or DMF. Studies show that the combination of using NaHCO 3 as the base and NMP as the solvent gives the best results with regard to conversion and cleanness of the reaction profile. Finally, after purification by recrystallization, for example in toluene, linagliptin is obtained with a yield of 77% and a purity of 99.2%.
スキーム２
リナグリプチンの別の調製方法が下記のスキーム３に概説される。一実施態様において、本発明は下記のスキーム３に実質的に示されるリナグリプチンを調製するための多工程合成方法に関する。その他の実施態様において、本発明はスキーム３の個々の工程のそれぞれ及びスキーム３の二つ以上の連続工程のあらゆる組み合わせに関する。また、本発明は、例えば、スキーム３に示される、中間体化合物に関する。
更に詳しい例において、ヨージド類似体(17)が(R)-3-アミノピペリジン二塩酸塩(13)との直接カップリングに使用されてリナグリプチンを調製してもよい（スキーム３）。
その合成は、例えば、NIS による3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (7)のヨウ素化で開始して化合物14を約91％の収率で得てもよく、これが続いて、例えば、好適な塩基及び好適な溶媒の存在下で、例えば、Na2CO3の存在下でNMP 中で1-ブロモ-2-ブチン(15) でアルキル化されて化合物16を97％の収率で得てもよい。次いで、化合物16が好適な塩基及び好適な溶媒の存在下で、例えば、Na2CO3の存在下でNMP 中で2-クロロメチル-4-メチル-キナゾリン(11)と反応させられて化合物17を65％の収率で得てもよい。
リナグリプチンを生成するための化合物17と(R)-3-アミノピペリジン二塩酸塩(13)のカップリング反応はNMP 、DMSO、DMAc、又はDMF のような異なる種類の高極性溶媒中で作業し得る。また、異なる種類の塩基がこの反応に使用でき、K2CO3 、Na2CO3、NaHCO3、又はKHCO3 が挙げられるが、これらに限定されない。本発明者らの研究は溶媒としてのDMSOと塩基としてのNaHCO3の組み合わせが反応転化率及び反応プロフィールのきれいさに関して最良の結果を与えることを示す。最後に、例えば、カラムクロマトグラフィーによる精製後に、リナグリプチンが54％の収率で99.0％の純度で得られる。
Another method for preparing linagliptin is outlined in Scheme 3 below. In one embodiment, the present invention relates to a multi-step synthetic method for preparing linagliptin substantially as shown in Scheme 3 below. In other embodiments, the invention relates to each of the individual steps of Scheme 3 and any combination of two or more sequential steps of Scheme 3. The present invention also relates to an intermediate compound shown in Scheme 3, for example.
In a more detailed example, iodide analog (17) may be used for direct coupling with (R) -3-aminopiperidine dihydrochloride (13) to prepare linagliptin (Scheme 3).
The synthesis may begin, for example, by iodination of 3-methyl-3,7-dihydro-purine-2,6-dione (7) with NIS to give compound 14 in about 91% yield, This is followed by alkylation of compound 16 with 1-bromo-2-butyne (15) in NMP, for example, in the presence of a suitable base and a suitable solvent, for example, in the presence of Na 2 CO 3. % Yield. Compound 16 is then reacted with 2-chloromethyl-4-methyl-quinazoline (11) in the presence of a suitable base and a suitable solvent, for example, NMP in the presence of Na 2 CO 3 to give compound 17 May be obtained in a yield of 65%.
The coupling reaction of compound 17 and (R) -3-aminopiperidine dihydrochloride (13) to produce linagliptin can work in different types of highly polar solvents such as NMP, DMSO, DMAc, or DMF . Also, different types of bases can be used for this reaction, including but not limited to K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , or KHCO 3 . Our study shows that the combination of DMSO as solvent and NaHCO 3 as base gives the best results in terms of reaction conversion and cleanness of the reaction profile. Finally, for example after purification by column chromatography, linagliptin is obtained with a yield of 54% and a purity of 99.0%.
スキーム３
化合物９又は化合物16をそれぞれ調製するための化合物７又は化合物14のアルキル化反応は、以下のように表し得る。本発明者らの研究に基づいて、使用される脱離基Ｘはこの反応でBr、Ｉ、OMs 、又はOTs のいずれであってもよい。
或る実施態様において、本発明は単離された形態、例えば、固体形態、無定形形態、凍結乾燥形態又は結晶性形態の示される中間体又は最終化合物に関する。
或る実施態様において、本発明は溶液形態（例えば、反応溶媒中に存在する）の示される中間体又は最終化合物に関する。
更に、本発明は本発明のプロセス又は方法により得られる、又は得られた示される中間体又は最終化合物に関する。
実施態様において、本発明は本明細書に記載された（反応）溶媒、例えば、トルエンから単離された（例えば、結晶化された）リナグリプチンに関する。
従って、本発明は更に下記の特別な実施態様1-10に関する。
1.式 (I)
前記方法が式(II)
の化合物を必要により好適な塩基の存在下で、
必要により好適な溶媒の存在下で
式 (III)
In certain embodiments, the present invention relates to the indicated intermediate or final compound in solution form (eg present in the reaction solvent).
The present invention further relates to the indicated intermediates or final compounds obtained or obtained by the process or method of the present invention.
In an embodiment, the present invention relates to linagliptin isolated (eg, crystallized) from the (reaction) solvent described herein, eg, toluene.
Accordingly, the present invention further relates to the following special embodiments 1-10.
1.Formula (I)
Said method is represented by formula (II)
In the presence of a suitable base, if necessary
Formula (III) in the presence of a suitable solvent if necessary
2.式 (I)の化合物が下記の式 (I*):
3.反応に使用される式 (III)の3-アミノピペリジンが
4.好適な塩基がNa2CO3、K2CO3 、NaHCO3又はKHCO3 である、実施態様１、２又は３記載の方法。
5.好適な溶媒がNMP 、DMSO、DMAc又はDMF を含む、実施態様１、２、３又は４記載の方法。
6.ＸがClである、実施態様１、２、３、４又は５記載の方法。
7.ＸがClであり、好適な塩基がNaHCO3であり、かつ好適な溶媒がNMP である、実施態様１、２、３、４又は５記載の方法。
8.ＸがＩである、実施態様１、２、３、４又は５記載の方法。
9.ＸがＩであり、好適な塩基がNaHCO3であり、かつ好適な溶媒がDMSOである、実施態様１、２、３、４又は５記載の方法。
10. 反応を上昇された反応温度、例えば、20℃から120 ℃まで、好ましくは40℃〜110 ℃で行なう、実施態様１から９のいずれか一つに記載の方法。
11. 更に式 (I)の化合物を好適な溶媒（例えば、トルエン）又は溶媒の混合物から（再）結晶化することを含む、実施態様１から10のいずれか一つに記載の方法。
4. The method according to embodiment 1, 2 or 3, wherein the suitable base is Na 2 CO 3 , K 2 CO 3 , NaHCO 3 or KHCO 3 .
5. The method of embodiment 1, 2, 3 or 4 wherein the suitable solvent comprises NMP, DMSO, DMAc or DMF.
6. The method of embodiment 1, 2, 3, 4 or 5 wherein X is Cl.
7. The process of embodiment 1, 2, 3, 4 or 5 wherein X is Cl, the preferred base is NaHCO 3 and the preferred solvent is NMP.
8. The method of embodiment 1, 2, 3, 4 or 5 wherein X is I.
9. The method of embodiment 1, 2, 3, 4 or 5 wherein X is I, the preferred base is NaHCO 3 and the preferred solvent is DMSO.
10. Process according to any one of embodiments 1 to 9, wherein the reaction is carried out at an elevated reaction temperature, for example from 20 ° C to 120 ° C, preferably from 40 ° C to 110 ° C.
11. The process according to any one of embodiments 1-10, further comprising (re) crystallization of the compound of formula (I) from a suitable solvent (eg toluene) or a mixture of solvents.
本発明の中間体及び最終化合物は一般に知られている合成の方法を使用して、又は既知の操作と類似もしくは同様にして得られてもよい。好ましくは、関係する中間体及び最終化合物が以下の更に詳細な実施例に記載される本発明の下記の方法により得られてもよい。
プロセス工程は例により本明細書に実質的に記載されたように行なわれてもよい。本発明のプロセス又は方法は記載された中間体を、好適には本明細書に開示されえた条件下で（例えば、示された試薬及び／又は溶媒及び／又は温度等を使用することにより）適当な反応パートナーで変換及び／又は反応させる一つ以上の工程を含んでもよい。
最適反応条件及び反応時間は使用される特別な反応体に応じて変化してもよい。特に明記されない限り、溶媒、温度、圧力、及びその他の反応条件は当業者により直ぐに選択し得る。特別な操作が合成実施例部分に提示される。典型的には、反応進行が所望ならばガスクロマトグラフィー(GC)、高圧液体クロマトグラフィー(HPLC)又は薄層クロマトグラフィーにより監視し得る。
The intermediates and final compounds of the present invention may be obtained using generally known synthetic methods or analogously or similarly to known procedures. Preferably, the relevant intermediates and final compounds may be obtained by the following methods of the invention as described in the more detailed examples below.
The process steps may be performed substantially as described herein by way of example. The process or method of the present invention is suitable for the described intermediates, preferably under the conditions disclosed herein (eg, by using the indicated reagents and / or solvents and / or temperature, etc.). One or more steps of conversion and / or reaction with various reaction partners may be included.
Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise stated, solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art. Special operations are presented in the synthesis examples section. Typically, if reaction progress is desired, it can be monitored by gas chromatography (GC), high pressure liquid chromatography (HPLC) or thin layer chromatography.
合成実施例
本発明が更に充分に理解されるために、下記の実施例が示される。これらの実施例は本発明の好ましい（独立又は従属の）実施態様を説明する目的のためであり、本発明の範囲を限定すると何ら見なされるべきではない。
実施例 1: 7-ブト -2-インイル-3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (9)の調製
Example 1: Preparation of 7-but-2-ynyl-3-methyl-3,7-dihydro-purine-2,6-dione (9)
50℃のNMP 140 mL中の3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (7) 20.0 g 及びKHCO3 13.2 g の懸濁液に、NMP 60 mL 中のメタンスルホン酸ブト-2-インイルエステル (8) 20.5 gの溶液を15分間で仕込んだ。その反応混合物を50℃で7.5 時間撹拌した。次いで、合計400 mLの水を滴下して添加した。その反応混合物を室温に冷却し、１時間撹拌した。生成物を濾過により集め、水200 mLで洗浄し、次いで真空で乾燥させた。合計24.76 g (収率94%)の化合物 9を白色の固体として97.6% のHPLC純度で得た。1H NMR (500 MHz, D2O): δ 7.46 (s, 1H), 4.61 (d, 3H, J = 2.0 Hz), 3.03 (s, 3H), 1.57 (t, 3H, J = 2.0 Hz); 13C NMR (125 MHz, D2O): δ 164.87, 159.51, 149.98, 139.86, 108.56, 84.33, 71.44, 36.52, 29.22, 2.52; 質量(m/z): 219.1 (M+H)+, 241.1 (M+Na)+. To a suspension of 20.0 g 3-methyl-3,7-dihydro-purine-2,6-dione (7) and 13.2 g KHCO 3 in 140 mL NMP at 50 ° C. -2-Inyl ester (8) A solution of 20.5 g was charged in 15 minutes. The reaction mixture was stirred at 50 ° C. for 7.5 hours. A total of 400 mL of water was then added dropwise. The reaction mixture was cooled to room temperature and stirred for 1 hour. The product was collected by filtration, washed with 200 mL water and then dried in vacuo. A total of 24.76 g (94% yield) of compound 9 was obtained as a white solid with 97.6% HPLC purity. 1 H NMR (500 MHz, D 2 O): δ 7.46 (s, 1H), 4.61 (d, 3H, J = 2.0 Hz), 3.03 (s, 3H), 1.57 (t, 3H, J = 2.0 Hz) ; 13 C NMR (125 MHz, D 2 O): δ 164.87, 159.51, 149.98, 139.86, 108.56, 84.33, 71.44, 36.52, 29.22, 2.52; mass (m / z): 219.1 (M + H) + , 241.1 (M + Na) + .
実施例 2: 7-ブト -2-インイル-8-クロロ-3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (10)の調製
DMF 245 mL中の7-ブト -2-インイル-3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (9) 24.5 g の溶液に、合計20.6 gのNCS (N-クロロスクシンイミド) を仕込んだ。その反応混合物を70℃（内部温度）で４時間撹拌し、次いで50℃に冷却した。合計368 mLの水をその反応混合物に滴下して添加した。得られる懸濁液を室温に冷却し、30分間撹拌した。生成物を濾過により集め、水100 mLで洗浄し、次いで真空で乾燥させた。合計23.4 g (収率83%)の化合物10を明褐色の固体として97.0% のHPLC純度で得た。1H NMR (500 MHz, DMSO-d6): δ 7.46 (s, 1H), 4.61 (d, 3H, J = 2.0 Hz), 3.03 (s, 3H), 1.57 (t, 3H, J = 2.0 Hz); 13C NMR (125 MHz, DMSO-d6): δ 153.96, 150.42, 148.13, 137.56, 107.07, 81.88, 72.15, 35.37, 28.53, 2.97;質量 (m/z): 253.1 (M+H)+, 275.0 (M+Na)+. 7-But-2-inyl-3-methyl-3,7-dihydro-purine-2,6-dione in 245 mL of DMF (9) In a solution of 24.5 g, 20.6 g of NCS (N-chlorosuccinimide) Was charged. The reaction mixture was stirred at 70 ° C. (internal temperature) for 4 hours and then cooled to 50 ° C. A total of 368 mL of water was added dropwise to the reaction mixture. The resulting suspension was cooled to room temperature and stirred for 30 minutes. The product was collected by filtration, washed with 100 mL water and then dried in vacuo. A total of 23.4 g (83% yield) of compound 10 was obtained as a light brown solid with 97.0% HPLC purity. 1 H NMR (500 MHz, DMSO-d 6 ): δ 7.46 (s, 1H), 4.61 (d, 3H, J = 2.0 Hz), 3.03 (s, 3H), 1.57 (t, 3H, J = 2.0 Hz ); 13 C NMR (125 MHz, DMSO-d 6 ): δ 153.96, 150.42, 148.13, 137.56, 107.07, 81.88, 72.15, 35.37, 28.53, 2.97; Mass (m / z): 253.1 (M + H) + , 275.0 (M + Na) + .
実施例 3: 7-ブト -2-インイル-8-クロロ-3-メチル-1-(4-メチル-キナゾリン-2-イルメチル)-3,7-ジヒドロ-プリン-2,6-ジオン (12)の調製
合計23.4 gの7-ブト -2-インイル-8-クロロ-3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (10) 、2-クロロメチル-4-メチル-キナゾリン (11) 18.2 g 、Na2CO3 10.8 g 及びNMP70 mL を250 mLの３口丸底フラスコに添加した。得られる反応混合物を100 ℃に加熱し、４時間撹拌し、次いで60℃に冷却した。合計140 mLのEtOH及びH2O 140 mLを一緒に混合し、その反応混合物に20分間で徐々に添加し、続いて酢酸11.2 gを添加した。得られる懸濁液を60℃で30分間撹拌し、次いで25℃に冷却し、更に30分間撹拌した。生成物を濾過により集め、水45 mL とEtOH 45 mLの混合物で洗浄し、真空で乾燥させた。合計29.3 g (収率78%)の化合物 12 を白色の固体として91.2% のHPLC純度で得た。1H NMR (500 MHz, DMSO-d6): δ 8.25 (d, 1H, J = 8.5 Hz), 7.92 (t, 1H, J = 8.0 Hz), 7.81 (d, 1H, J = 8.5Hz), 7.68 (t, 1H, J = 7.5 Hz), 5.35 (s, 2H), 5.14 (d, 2H, J = 2.0 Hz), 3.43 (s, 3H), 2.89 (s, 3H), 1.79 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 169.50, 160.87, 153.94, 151.06, 149.49, 147.49, 138.73, 134.66, 128.33, 127.74, 126.24, 123.00, 107.19, 82.51, 72.62, 46.28, 36.05, 30.10, 22.06, 3.46;質量 (m/z): 409.1 (M+H)+. 23.4 g total 7-but-2-ynyl-8-chloro-3-methyl-3,7-dihydro-purine-2,6-dione (10), 2-chloromethyl-4-methyl-quinazoline (11) 18.2 g, 10.8 g Na 2 CO 3 and 70 mL NMP were added to a 250 mL 3-neck round bottom flask. The resulting reaction mixture was heated to 100 ° C., stirred for 4 hours, and then cooled to 60 ° C. A total of 140 mL EtOH and 140 mL H 2 O were mixed together and added slowly to the reaction mixture over 20 minutes followed by 11.2 g acetic acid. The resulting suspension was stirred at 60 ° C. for 30 minutes, then cooled to 25 ° C. and stirred for an additional 30 minutes. The product was collected by filtration, washed with a mixture of 45 mL water and 45 mL EtOH, and dried in vacuo. A total of 29.3 g (78% yield) of compound 12 was obtained as a white solid with 91.2% HPLC purity. 1 H NMR (500 MHz, DMSO-d 6 ): δ 8.25 (d, 1H, J = 8.5 Hz), 7.92 (t, 1H, J = 8.0 Hz), 7.81 (d, 1H, J = 8.5 Hz), 7.68 (t, 1H, J = 7.5 Hz), 5.35 (s, 2H), 5.14 (d, 2H, J = 2.0 Hz), 3.43 (s, 3H), 2.89 (s, 3H), 1.79 (s, 3H ); 13 C NMR (125 MHz, DMSO-d 6 ): δ 169.50, 160.87, 153.94, 151.06, 149.49, 147.49, 138.73, 134.66, 128.33, 127.74, 126.24, 123.00, 107.19, 82.51, 72.62, 46.28, 36.05, 30.10, 22.06, 3.46; Mass (m / z): 409.1 (M + H) + .
実施例 4: リナグリプチンの調製
合計10.0 gの7-ブト -2-インイル-8-クロロ-3-メチル-1-(4-メチル-キナゾリン-2-イルメチル)-3,7-ジヒドロ-プリン-2,6-ジオン (12) 、(R)-3-アミノピペリジン二塩酸塩 (13) 5.1 g 、NMP 30 mL 及び重炭酸ナトリウム7.2 g を250 mLの３口丸底フラスコに添加した。その反応混合物を90℃に加熱し、２時間撹拌し、次いで40℃に冷却した。次いで、合計90 mL のジクロロメタン (DCM)及び水90 mL を仕込み、その反応混合物を25分間撹拌した。有機相を集め、水相をDCM 更に30 mL で抽出した。合わせた有機相をH2O 90 mL で３回洗浄し（それぞれの洗浄は20分以上を要する）、次いで酢酸溶液122.9 g (水中2.4質量％) とともに30分間撹拌した。集められた水相にDCM 120 mL及び1 N NaOH水溶液49 mL を仕込んだ。得られる混合物を30分間撹拌した。有機相を集め、濃縮、乾燥した。得られる黄色の粗生成物をトルエン30 mL 中で懸濁させ、加熱、還流し、１時間撹拌した。次いでそれを70℃に冷却し、１時間撹拌した。次に、それを50℃に徐々に冷却し、１時間撹拌した。最後に、それを25℃に徐々に冷却し、２時間撹拌した。生成物を濾過により集め、真空で乾燥させた。合計8.9 g (収率77%) のリナグリプチンを淡黄色の固体として99.2% のHPLC純度で得た。1H NMR (500 MHz, DMSO-d6): δ 8.22 (d, 1H, J = 8.0 Hz), 7.89 (m, 1H), 7.80 (d, 1H, J = 8.5 Hz), 7.68 (m, 1H), 5.32 (s, 2H), 4.90 (s, 2H), 3.59-3.67 (m, 2H), 3.00 (m, 1H), 2.88 (s, 3H), 2.81-2.85 (m, 1H), 2.74-2.78 (m, 1H), 1.78-1.88 (m, 5H), 1.59-1.66 (m, 3H), 1.20-1.27 (m, 1H); 13C NMR (125 MHz, DMSO-d6): δ 168.78, 160.97, 156.11, 153.20, 150.90, 149.01, 147.71, 134.01, 127.83, 127.08, 125.67, 122.45, 103.17, 81.10, 73.74, 57.61, 49.54, 47.27, 45.53, 35.47, 33.23, 29.39, 23.28, 21.53, 3.05;質量 (m/z): 473.2 (M+H)+. Total 10.0 g of 7-but-2-ynyl-8-chloro-3-methyl-1- (4-methyl-quinazolin-2-ylmethyl) -3,7-dihydro-purine-2,6-dione (12) , (R) -3-Aminopiperidine dihydrochloride (13) 5.1 g, NMP 30 mL and sodium bicarbonate 7.2 g were added to a 250 mL 3-neck round bottom flask. The reaction mixture was heated to 90 ° C., stirred for 2 hours and then cooled to 40 ° C. A total of 90 mL of dichloromethane (DCM) and 90 mL of water were then charged and the reaction mixture was stirred for 25 minutes. The organic phase was collected and the aqueous phase was extracted with an additional 30 mL of DCM. The combined organic phases were washed 3 times with 90 mL H 2 O (each wash takes 20 minutes or more) and then stirred with 122.9 g acetic acid solution (2.4% by weight in water) for 30 minutes. The collected aqueous phase was charged with 120 mL of DCM and 49 mL of 1 N aqueous NaOH. The resulting mixture was stirred for 30 minutes. The organic phase was collected, concentrated and dried. The resulting yellow crude product was suspended in 30 mL of toluene, heated to reflux and stirred for 1 hour. It was then cooled to 70 ° C. and stirred for 1 hour. It was then gradually cooled to 50 ° C. and stirred for 1 hour. Finally, it was gradually cooled to 25 ° C. and stirred for 2 hours. The product was collected by filtration and dried in vacuo. A total of 8.9 g (77% yield) of linagliptin was obtained as a pale yellow solid with 99.2% HPLC purity. 1 H NMR (500 MHz, DMSO-d 6 ): δ 8.22 (d, 1H, J = 8.0 Hz), 7.89 (m, 1H), 7.80 (d, 1H, J = 8.5 Hz), 7.68 (m, 1H ), 5.32 (s, 2H), 4.90 (s, 2H), 3.59-3.67 (m, 2H), 3.00 (m, 1H), 2.88 (s, 3H), 2.81-2.85 (m, 1H), 2.74- 2.78 (m, 1H), 1.78-1.88 (m, 5H), 1.59-1.66 (m, 3H), 1.20-1.27 (m, 1H); 13 C NMR (125 MHz, DMSO-d 6 ): δ 168.78, 160.97, 156.11, 153.20, 150.90, 149.01, 147.71, 134.01, 127.83, 127.08, 125.67, 122.45, 103.17, 81.10, 73.74, 57.61, 49.54, 47.27, 45.53, 35.47, 33.23, 29.39, 23.28, 21.53, 3.05; mass ( m / z): 473.2 (M + H) + .
実施例 5: 8-ヨード-3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (14)の調製
合計10.0 gの3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン(7), NIS (N-ヨードスクシンイミド) 17.9 g及びDMSO 40 mLを反応器に仕込んだ。得られる溶液を40℃で26時間撹拌した。合計60 mL の水を滴下して添加した。得られる混合物を40℃で30分間撹拌した。生成物を濾過により集め、40 mL の1:1 のDMSO +水及び40 mL の水のそれぞれで洗浄した。次いでそれを真空で乾燥させた。合計16.3 g (収率91%) の化合物 14 を黄色の固体として94%のHPLC純度で得た。1H NMR (500 MHz, D2O): δ 2.69 (s, 3H); 13C NMR (125 MHz, D2O): δ 164.05, 156.11, 150.53, 118.40, 100.61, 27.40;質量 (m/z): 292.9 (M+H)+. A total of 10.0 g 3-methyl-3,7-dihydro-purine-2,6-dione (7), NIS (N-iodosuccinimide) 17.9 g and DMSO 40 mL were charged to the reactor. The resulting solution was stirred at 40 ° C. for 26 hours. A total of 60 mL of water was added dropwise. The resulting mixture was stirred at 40 ° C. for 30 minutes. The product was collected by filtration and washed with 40 mL of 1: 1 DMSO + water and 40 mL of water, respectively. It was then dried in vacuo. A total of 16.3 g (91% yield) of compound 14 was obtained as a yellow solid with 94% HPLC purity. 1 H NMR (500 MHz, D 2 O): δ 2.69 (s, 3H); 13 C NMR (125 MHz, D 2 O): δ 164.05, 156.11, 150.53, 118.40, 100.61, 27.40; mass (m / z ): 292.9 (M + H) + .
実施例 6: 7-ブト -2-インイル-8-ヨード-3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (16)の調製
合計7.2 g の8-ヨード-3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (14) 、KHCO3 3.0 g 及びNMP 60 mL を250 mLの丸底フラスコに仕込んだ。その反応混合物を55℃に加熱した。NMP 10 mL 中の1-ブロモ-2-ブチン (15) 3.93 g の溶液を滴下して添加した。その反応混合物を55℃で２時間撹拌した。合計70 mL の水をその反応混合物に仕込んだ。その反応混合物を60℃で20分間撹拌した。生成物を濾過により集め、真空で乾燥させた。合計8.3 g (収率97%)の化合物 16 を白色の固体として98.0% のHPLC純度で得た。1H NMR (500 MHz, DMSO-d6): δ 11.26 (s, 1H), 5.00 (d, 1H, J = 2.5 Hz), 3.31 (s, 3H), 1.80 (t, 3H, J = 2.5Hz); 13C NMR (125 MHz, DMSO-d6): δ 153.55, 150.69, 109.08, 104.50, 81.90, 72.62, 28.51, 2.90;質量 (m/z): 345.0 (M+H)+, 366.9 (M+Na)+. A total of 7.2 g of 8-iodo-3-methyl-3,7-dihydro-purine-2,6-dione (14), 3.0 g of KHCO 3 and 60 mL of NMP were charged into a 250 mL round bottom flask. The reaction mixture was heated to 55 ° C. A solution of 3.93 g of 1-bromo-2-butyne (15) in 10 mL of NMP was added dropwise. The reaction mixture was stirred at 55 ° C. for 2 hours. A total of 70 mL of water was charged to the reaction mixture. The reaction mixture was stirred at 60 ° C. for 20 minutes. The product was collected by filtration and dried in vacuo. A total of 8.3 g (97% yield) of compound 16 was obtained as a white solid with 98.0% HPLC purity. 1 H NMR (500 MHz, DMSO-d 6 ): δ 11.26 (s, 1H), 5.00 (d, 1H, J = 2.5 Hz), 3.31 (s, 3H), 1.80 (t, 3H, J = 2.5Hz ); 13 C NMR (125 MHz, DMSO-d 6 ): δ 153.55, 150.69, 109.08, 104.50, 81.90, 72.62, 28.51, 2.90; Mass (m / z): 345.0 (M + H) + , 366.9 (M + Na) + .
実施例 7: 7-ブト -2-インイル-8-ヨード-3-メチル-1-(4-メチル-キナゾリン-2-イルメチル)-3,7-ジヒドロ-プリン-2,6-ジオン (17) の調製
合計6.88 gの7-ブト -2-インイル-8-ヨード-3-メチル-3,7-ジヒドロ-プリン-2,6-ジオン (16) 、Na2CO3 2.33 g、2-クロロメチル-4-メチル-キナゾリン (11) 3.85 g及びNMP 20 mLを250 mLの３口丸底フラスコに仕込んだ。その反応混合物を90℃に加熱し、11時間撹拌した。合計40 mL のEtOHを添加し、続いて水40 mL 及び酢酸2.4 g を添加した。得られる懸濁液を60℃に冷却し、0.5 時間撹拌した。次いでそれを25℃に冷却した。生成物を濾過により集め、真空で乾燥させた。合計6.52 g (収率65%)の化合物 17 を淡黄色の固体として97% のHPLC純度で得た。1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H, J = 7.5 Hz), 7.91 (m, 1H), 7.81 (d, 1H, J = 8.0 Hz), 7.68 (m, 1H), 5.34 (s, 2H), 5.06 (s, 2H), 3.43 (s, 3H), 2.88 (s, 3H), 1.79 (t, 3H, J = 2.4Hz); 13C NMR (100 MHz, DMSO-d6): δ 169.50, 160.95, 153.54, 151.12, 150.02, 149.46, 134.64, 128.34, 127.73, 126.26, 122.99, 109.10, 106.06, 82.38, 73.23, 46.24, 39.02, 30.03, 22.07, 3.50;質量 (m/z): 501.0 (M+H)+. 6.88 g total 7-but-2-ynyl-8-iodo-3-methyl-3,7-dihydro-purine-2,6-dione (16), Na 2 CO 3 2.33 g, 2-chloromethyl-4 -Methyl-quinazoline (11) 3.85 g and NMP 20 mL were charged into a 250 mL 3-neck round bottom flask. The reaction mixture was heated to 90 ° C. and stirred for 11 hours. A total of 40 mL EtOH was added, followed by 40 mL water and 2.4 g acetic acid. The resulting suspension was cooled to 60 ° C. and stirred for 0.5 hour. It was then cooled to 25 ° C. The product was collected by filtration and dried in vacuo. A total of 6.52 g (65% yield) of compound 17 was obtained as a pale yellow solid with 97% HPLC purity. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.25 (d, 1H, J = 7.5 Hz), 7.91 (m, 1H), 7.81 (d, 1H, J = 8.0 Hz), 7.68 (m, 1H ), 5.34 (s, 2H), 5.06 (s, 2H), 3.43 (s, 3H), 2.88 (s, 3H), 1.79 (t, 3H, J = 2.4Hz); 13 C NMR (100 MHz, DMSO -d 6 ): δ 169.50, 160.95, 153.54, 151.12, 150.02, 149.46, 134.64, 128.34, 127.73, 126.26, 122.99, 109.10, 106.06, 82.38, 73.23, 46.24, 39.02, 30.03, 22.07, 3.50; mass (m / z): 501.0 (M + H) + .
実施例 8: リナグリプチンの調製
合計5.0 g の7-ブト -2-インイル-8-ヨード-3-メチル-1-(4-メチル-キナゾリン-2-イルメチル)-3,7-ジヒドロ-プリン-2,6-ジオン (17) 、(R)-3-アミノピペリジン二塩酸塩 (13) 1.9 g 、DMSO 15 mL 及びNaHCO3 2.77 g を３口丸底フラスコに仕込んだ。その混合物を110 ℃に加熱し、４時間撹拌し、次いで40℃に冷却した。合計45 mL の水を添加し、続いてジクロロメタン45 mL を添加した。その混合物を15分間撹拌した。有機相を集め、水相をジクロロメタン30 mL で抽出した。合わせた有機相を水20 mL で洗浄し、次いで濃縮、乾燥した。粗生成物をカラムクロマトグラフィーにより精製した。合計2.53 g (収率54%)のリナグリプチンを淡黄色の固体として99.0% の純度で得た。1H NMR (500 MHz, DMSO-d6): δ 8.22 (d, 1H, J = 8.0 Hz), 7.89 (m, 1H), 7.80 (d, 1H, J = 8.5 Hz), 7.68 (m, 1H), 5.32 (s, 2H), 4.90 (s, 2H), 3.59-3.67 (m, 2H), 3.00 (m, 1H), 2.88 (s,3H), 2.81-2.85 (m, 1H), 2.74-2.78 (m, 1H), 1.78-1.88 (m, 5H), 1.59-1.66 (m, 3H), 1.20-1.27 (m, 1H); 13C NMR (125 MHz, DMSO-d6): δ 168.78, 160.97, 156.11, 153.20, 150.90, 149.01, 147.71, 134.01, 127.83, 127.08, 125.67, 122.45, 103.17, 81.10, 73.74, 57.61, 49.54, 47.27, 45.53, 35.47, 33.23, 29.39, 23.28, 21.53, 3.05;質量 (m/z): 473.2 (M+H)+. Total 5.0 g 7-but-2-ynyl-8-iodo-3-methyl-1- (4-methyl-quinazolin-2-ylmethyl) -3,7-dihydro-purine-2,6-dione (17) , (R) -3-aminopiperidine dihydrochloride (13) 1.9 g, DMSO 15 mL and NaHCO 3 2.77 g were charged into a three-necked round bottom flask. The mixture was heated to 110 ° C., stirred for 4 hours and then cooled to 40 ° C. A total of 45 mL of water was added, followed by 45 mL of dichloromethane. The mixture was stirred for 15 minutes. The organic phase was collected and the aqueous phase was extracted with 30 mL of dichloromethane. The combined organic phases were washed with 20 mL water and then concentrated to dryness. The crude product was purified by column chromatography. A total of 2.53 g (54% yield) of linagliptin was obtained as a pale yellow solid in 99.0% purity. 1 H NMR (500 MHz, DMSO-d 6 ): δ 8.22 (d, 1H, J = 8.0 Hz), 7.89 (m, 1H), 7.80 (d, 1H, J = 8.5 Hz), 7.68 (m, 1H ), 5.32 (s, 2H), 4.90 (s, 2H), 3.59-3.67 (m, 2H), 3.00 (m, 1H), 2.88 (s, 3H), 2.81-2.85 (m, 1H), 2.74- 2.78 (m, 1H), 1.78-1.88 (m, 5H), 1.59-1.66 (m, 3H), 1.20-1.27 (m, 1H); 13 C NMR (125 MHz, DMSO-d 6 ): δ 168.78, 160.97, 156.11, 153.20, 150.90, 149.01, 147.71, 134.01, 127.83, 127.08, 125.67, 122.45, 103.17, 81.10, 73.74, 57.61, 49.54, 47.27, 45.53, 35.47, 33.23, 29.39, 23.28, 21.53, 3.05; mass ( m / z): 473.2 (M + H) + .
Claims (10)
式 (II)
の化合物を、
必要により好適な塩基の存在下で、
必要により好適な溶媒の存在下で
式 (III)
A compound of
If necessary in the presence of a suitable base,
If necessary, in the presence of a suitable solvent, the compound of formula (III)
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| CN107936023B (en) * | 2017-12-28 | 2020-09-04 | 安庆奇创药业有限公司 | Synthetic method of linagliptin intermediate |
| IT201800005383A1 (en) | 2018-05-15 | 2019-11-15 | INTERMEDIATES AND PROCESSES FOR THE PREPARATION OF LINAGLIPTIN AND ITS SALTS | |
| CN111574463B (en) * | 2019-02-19 | 2023-07-14 | 鲁南制药集团股份有限公司 | Rivastigmine intermediate compound IV |
| US20210221792A1 (en) * | 2020-01-16 | 2021-07-22 | Hanmi Pharm Co., Ltd. | Convergent synthesis of poziotinib derivative |
| WO2023156675A1 (en) | 2022-02-21 | 2023-08-24 | Krka, D.D., Novo Mesto | Process for purification of linagliptin |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003104229A1 (en) * | 2002-06-06 | 2003-12-18 | エーザイ株式会社 | Novel fused imidazole derivative |
| JP2004502690A (en) * | 2000-07-04 | 2004-01-29 | ノボ ノルディスク アクティーゼルスカブ | Heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
| JP2006503013A (en) * | 2002-08-21 | 2006-01-26 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 8- [3-Amino-piperidin-1-yl] -xanthine, its preparation and its use as a pharmaceutical composition |
| JP2008519005A (en) * | 2004-11-05 | 2008-06-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Process for producing chiral 8- (3-amino-piperidin-1-yl) -xanthine |
| WO2013098775A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Improved process for preparation of pure linagliptin |
| CN103450201A (en) * | 2012-05-30 | 2013-12-18 | 博瑞生物医药技术(苏州)有限公司 | Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine |
| WO2014009970A2 (en) * | 2012-07-09 | 2014-01-16 | Hetero Research Foundation | Linagliptin solid dispersion |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319483B (en) | 2012-10-19 | 2016-08-03 | 药源药物化学（上海）有限公司 | A kind of preparation method of important intermediate of linagliptin |
| EP3974431A1 (en) * | 2015-06-25 | 2022-03-30 | Boehringer Ingelheim International GmbH | Process for the preparation of a xanthine-based compound |
-
2016
- 2016-06-24 EP EP21202357.6A patent/EP3974431A1/en active Pending
- 2016-06-24 WO PCT/EP2016/064692 patent/WO2016207364A1/en active Application Filing
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-
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- 2021-04-09 JP JP2021066411A patent/JP2021119142A/en not_active Withdrawn
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004502690A (en) * | 2000-07-04 | 2004-01-29 | ノボ ノルディスク アクティーゼルスカブ | Heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
| WO2003104229A1 (en) * | 2002-06-06 | 2003-12-18 | エーザイ株式会社 | Novel fused imidazole derivative |
| JP2006503013A (en) * | 2002-08-21 | 2006-01-26 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 8- [3-Amino-piperidin-1-yl] -xanthine, its preparation and its use as a pharmaceutical composition |
| JP2008519005A (en) * | 2004-11-05 | 2008-06-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Process for producing chiral 8- (3-amino-piperidin-1-yl) -xanthine |
| WO2013098775A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Improved process for preparation of pure linagliptin |
| CN103450201A (en) * | 2012-05-30 | 2013-12-18 | 博瑞生物医药技术(苏州)有限公司 | Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine |
| WO2014009970A2 (en) * | 2012-07-09 | 2014-01-16 | Hetero Research Foundation | Linagliptin solid dispersion |
Non-Patent Citations (1)
| Title |
|---|
| ECKHARDT M: "8-(3-(R)-AMINOPIPERIDIN-1-YL)-7-BUT-2-YNYL-3-METHYL-1-(4-METHYL-QUINAZOLIN-2-YLMETHYL)-以下備考", JOURNAL OF MEDICINAL CHEMISTRY, vol. V50 N26, JPN5012005598, 27 December 2007 (2007-12-27), US, pages 6450 - 6453, ISSN: 0004404285 * |
Also Published As
| Publication number | Publication date |
|---|---|
| US20180179207A1 (en) | 2018-06-28 |
| EP3974431A1 (en) | 2022-03-30 |
| EP3313841A1 (en) | 2018-05-02 |
| WO2016207364A1 (en) | 2016-12-29 |
| JP6901976B2 (en) | 2021-07-14 |
| US10253026B2 (en) | 2019-04-09 |
| JP2021119142A (en) | 2021-08-12 |
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